The Pima Indians of Arizona have the highest reported prevalence and incidence of non-insulin dependent diabetes mellitus (NIDDM) of any population in the world. Beginning in 1982, our section has studied a subset of this population to determine the etiologic factors that predispose non-diabetic individuals to develop the disease. Subjects are admitted yearly to the clinical research ward to undergo body composition analysis, an oral glucose tolerance test, an intravenous glucose tolerance tests, a standard mixed meal test, and a two-step hyperinsulinemic, euglycemic clamp to measure insulin action in vivo. Approximately 400 individuals have entered into the study and approximately 50 subjects have developed NIDDM. Subjects with NIDDM are characterized by; 1) obesity, 2) central obesity, 3) insulin resistance, 4) insulin secretory dysfunction, and 5) overproduction of glucose by the liver. Obesity, central obesity, fasting hyperinsulinemia, and insulin resistance are each major risk factors for the developement of NIDDM. The acute insulin response to a intravenous glucose bolus is an additional, but weaker predictor. The rate of post-absorptive of hepatic glucose production is not predictive of the disease.